The present invention relates to 3-carboxy quinoline derivatives, compositions and medicaments containing the same, as well as processes for the preparation and use of such compounds, compositions and medicaments. Such 3-carboxy quinoline derivatives are useful in the treatment of diseases associated with inappropriate YAK3 activity.
The YAK family of serine/threonine protein kinases, represent a novel family of dual specificity protein kinases with unique structural, enzymatic, and probably functional features (Becker and Joost (1999) Prog. Nucl. Acid Res. 62, 1-17). Four members of the YAK family have been identified by large scale screening of human cDNA libraries using a yeast YAK1 sequence, and have been termed h (human)Yak1, 2, 3, and 4. (See U.S. Pat. No. 5,972,606 (hYAK1), U.S. Pat. No. 6,001,623 (hYAK2), and U.S. Pat. No. 5,965,420 (hYAK3)) In the yeast S. cerevisiae YAK1 functions as a negative regulator of cell growth (Garrett, S., Menold, M. M., and Broach, J. (1991) Mol. Cell Biol. 11, 4045-4051). Deletion of the three PKA genes (tpk1, tpk2, and tpk3) in yeast causes cell cycle arrest at G1 while this growth defect is alleviated by removal of the YAK1 gene (Garrett, S., and Broach, J. (1989) Gene Dev. 3, 1336-1348). Recent data indicates that yYAK1 expression is controlled by two transcription factors MSN2/4 which are negatively regulated by PKA, thus yYAK1 acts downstream of PKA (Smith, A., Ward, M. P. and Garrett, S. (1998) EMBO J. 17, 3556-3564). While the means by which yYAK1 inhibits cell growth is still not known, overexpression of yYAK1 suppresses cell cycle arrest in late mitotic mutants (cdc15, cdc5, dbf2, and tem1) defective in anaphase-promoting complex (APC) (Jaspersen, S. L Charles, J. F., Tinker-Kulberg, R. L., and Morgan, D. O. (1998) Mol. Biol. of the Cell. 9, 2803-2817). Recent work in Dictyostelium has uncovered a yYAK1 homolog which is required for the transition from growth to development giving support to the involvement of this family of kinases in cell growth (Souza, G. M., Lu, S. and Kuspa, A. (1998) Development 125,
Northern analysis was carried out to determine the distribution of hYAK3 mRNA in human tissues. Membranes containing mRNA from multiple human tissues (Clontech #7760-1, #7759-1, and #7768-1) were hybridized to an hYAK3 probe and washed under high stringency conditions as directed. Hybridized mRNA was visualized by exposing the membranes to X-ray film. One major transcript at ˜2.5 kb was present in testis, and transcripts of 2.5, 8 and 10 kb were present in bone and fetal liver. The transcripts were not visible in any other tissues; however, dot blot analysis using a Human Master blot (Clontech #7770-1) indicated that hYAK3 is expressed in other tissues including skeletal muscle.
Investigations with primary cells and hematopoietic cell lines from both human and mouse indicate that cells of the erythroid lineage may predominantly account for the elevated hYAK3 expression. These data suggest that hYAK3 may have a lineage-specific function. In cell lines, hYAK3 is present at higher levels in cells with an erythroid phenotype than other hematopoietic lineages, including myeloid, monocytic and lymphoid cell lines. This profile is completely distinct from hYAK1, which has been observed only at low constitutive levels in hematopoietic cells and tissues. EPO-treatment of human bone marrow in vitro leads to induction and sustained expression of hYAK3 message and hYAK3 protein. Splenocytes from mice made anemic by phenylhydrazine treatment become enriched in erythroid progenitors and exhibit increased expression of hYAK3. Increases in both message and protein accompany induction of erythroid differentiation in UT7-EPO cells.
In yeast, yYAK is a negative regulator of growth via the cell cycle. Consequently, we would anticipate that hYAK3 participates in cell cycle control, and/or commitment to differentiation. We predict that an antagonist of hYAK3 would have a positive effect on cell growth. Our data indicates that it also may be involved in terminal differentiation and growth arrest in hematopoietic cells, especially in the erythroid lineage.
The present inventors have discovered novel 3-carboxy quinoline compounds, which are inhibitors of YAK3 activity. Such 3-carboxy quinoline derivatives are useful in the treatment of disorders associated with inappropriate YAK3 activity, especially diseases of the hematopoietic systems, including anemias due to renal insufficiency or to chronic disease, such as autoimmunity or cancer and drug-induced anemias, polycythemia, myelodysplastic syndrome, aplastic anemia and myelosuppression; cytopenia; neurodegeneration; and also for controlling male fertility, especially for the purpose of achieving contraception.